This application, in response to RFA-DA-04-014 Medication Development for Cannabis-Related Disorders, addresses cannabis dependence from two perspectives: 1) quantifying the acute, chronic and withdrawal effects of cannabis using brain imaging (EEG/ERP, fMRI and MRS) and 2) using these data to serve as a foundation for exploring new strategies for cannabis medication development. It is unclear how cannabis affects brain function, either acutely or after chronic use so knowledge of the changes in brain function during cannabis dependence and withdrawal will aid greatly in our understanding of the neurobiological bases of cannabis abuse and will thus serve as an important foundation for developing new medications to treat this disorder. New and improved brain imaging techniques such as fMRI and MRS offer us a unique opportunity to view these subtle, yet important changes in brain function. As a first step in devising a medication to treat cannabis dependence we propose to carefully document the effects of acutely administered cannabis on regional cerebral blood flow and brain chemistry. These effects will be compared to the acutely withdrawn brain and thus will serve as baselines to assess the efficacy of a novel medication, cytidine-5'- diphosphate choline (CDP-choline, citicoline) in reducing cannabis use, and reversing the psychomotor performance deficits, memory loss and sleep disorders that occur during cannabis intoxication and withdrawal. We chose citicoline based on our serendipitous findings that it reduces not only cocaine use in our ongoing clinical trial, but appears to reduce marihuana smoking as well. Our experiments capitalize on the results obtained in our ongoing clinical studies of cocaine-dependent subjects along with pilot MR data. If positive, these results could have important implications for the pharmacotherapy of cannabis dependence as well as primary and secondary prevention of neurobiological damage associated with chronic cannabis use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of cannabis dependence (and potentially on other drug dependence disorders). As multidisciplinary approaches to treating drug abuse have been the most successful, we will use a 2 x 2 design to test the combination of citicoline and cognitive behavioral therapy (CBT) for insomnia as an effective treatment for cannabis dependence. Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug dependent mothers, and adolescents.